Common Toxic Effects Research Articles

Liver-targeting chimeras as a potential modality for the treatment of liver diseases

Liver diseases pose significant challenges to global public health. In the realm of drug discovery and development, overcoming ‘on-target off-tissue’ effects remains a substantial barrier for various diseases. In this study, we have pioneered a Liver-Targeting Chimera (LIVTAC) approach using a proteolysis-targeting chimera (PROTAC) molecule coupled to the liver-specific asialoglycoprotein receptor (ASGPR) through an innovative linker attachment strategy for the precise induction of target protein degradation within the liver. As a proof-of-concept study, we designed XZ1606, a mammalian bromodomain and extra-terminal domain (BET)-targeting LIVTAC agent, which not only demonstrated enduring tumor suppression (over 2 months) in combination with sorafenib but also an improved safety profile, notably ameliorating the incidence of thrombocytopenia, a common and severe on-target dose-limiting toxic effect associated with conventional BET inhibitors. These encouraging results highlight the potential of LIVTAC as a versatile platform for addressing a broad spectrum of liver diseases.

Progress in Traditional Chinese and Western Medicine Treatment of Chemotherapy‐Induced Peripheral Neuropathy

In recent years, the incidence of malignant tumors rising rapidly, as targeted, immune treatment has brought the Gospel at the same time, due to the expensive drug, adapt to the limited, side effects make its clinical application is limited, so chemical therapy is still the cornerstone of the clinical treatment of malignant tumors. Chemotherapy‐induced peripheral neuropathy (CIPN) is a common toxic and side effect in the process of chemotherapy. Modern medicine has no good treatment and drugs for modern medicine, mainly prevention. With its unique thinking mode of syndrome differentiation and the multi-target characteristics of Traditional Chinese Medicine (TCM), TCM may provide new ideas for the treatment of CIPN. This paper reviews the pathogenesis of peripheral neurotoxicity induced by chemotherapy drugs and the diagnosis and treatment of traditional Chinese and Western medicine.

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma treated with intensity-modulated radiation therapy: A retrospective study with a 5-year follow-up.

e18003 Background: This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Methods: Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at the affiliated cancer hospital of Guizhou medical university. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a “MELODIE” multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n = 35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. Results: After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Conclusions: Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

Long-term survival, toxicities, and the role of chrono-chemotherapy with different infusion rates in locally advanced nasopharyngeal carcinoma patients treated with intensity-modulated radiation therapy: a retrospective study with a 5-year follow-up.

This study aimed to evaluate 5-year outcomes and the late toxicity profile of chrono-chemotherapy with different infusion rates in patients with locally advanced nasopharyngeal carcinoma (NPC). Our retrospective analysis included 70 patients with locally advanced NPC stages III and IVB (according to the 2010 American Joint Committee on Cancer staging system). Patients were treated with two cycles of induction chemotherapy (IC) before concurrent chemoradiotherapy (CCRT) at Guizhou Cancer Hospital. The IC with docetaxel, cisplatin (DDP) and fluorouracil regimen. Patients were divided into two groups during CCRT. Using a "MELODIE" multi-channel programmed pump, DDP (100 mg/m2) was administered for 12 hours from 10:00 am to 10:00 pm and repeated every 3 weeks for 2-3 cycles. DDP was administered at the peak period of 4:00 pm in the sinusoidal chrono-modulated infusion group (Arm A, n=35). The patients in Arm B received a constant rate of infusion. Both arms received radiotherapy through the same technique and dose fraction. The long-term survival and disease progression were observed. After a median follow-up of 82.8 months, the 5-year progression-free survival rate was 81.3% in Arm A and 79.6% in Arm B (P = 0.85). The 5-year overall survival rate was not significantly different between Arm A and Arm B (79.6% vs 85.3%, P = 0.79). The 5-year distant metastasis-free survival rate was 83.6% in Arm A and 84.6% in Arm B (P = 0.75). The 5-year local recurrence-free survival rate was 88.2% in Arm A and 85.3% in Arm B (P = 0.16). There were no late toxicities of grade 3-4 in either group. Both groups had grade 1-2 late toxicities. Dry mouth was the most common late toxic side effect, followed by hearing loss and difficulty in swallowing. There was no statistically significant difference between Arm A and Arm B in terms of side effects. Long-term analysis confirmed that in CCRT, cisplatin administration with sinusoidal chrono-modulated infusion was not superior to the constant infusion rate in terms of long-term toxicity and prognosis.

Neoadjuvant chemotherapy plus concurrent chemoradiotherapy versus concurrent chemoradiotherapy alone in elderly patients with stage III-IVa nasopharyngeal carcinoma: A real-world study based on medical comorbidities.

To evaluate the outcomes and toxicities of adding neoadjuvant chemotherapy (NAC) to concurrent chemoradiotherapy (CCRT) in elderly (≥65 years) patients with locoregionally advanced nasopharyngeal carcinoma (LANPC, stage III-IVa). Using an NPC-specific database, 245 elderly patients with stage III-IVa NPC, receiving CCRT +/- NAC, and an Adult Co-morbidity Evaluation 27 (ACE-27) score <2 were included. Recursive partitioning analysis (RPA) based on TNM stage and Epstein-Barr virus (EBV) DNA were applied for risk stratification. The primary end point was disease-free survival (DFS). Two risk groups were generated by the RPA model. In the high-risk group (EBV DNA < 4000 copy/ml with stage IVa & EBV DNA ≥4000 copy/ml with stage III-IVa), patients treated with NAC plus CCRT achieved improved 5-year DFS rates compared to those who received CCRT alone (56.9% vs. 29.4%; p = 0.003). But we failed to observe the survival benefit of additional NAC in the low-risk group (EBV DNA <4000 copy/ml with stage III). The most common severe acute toxic effects were leucopenia (46.8% vs. 24.4%) and neutropenia (43.7% vs. 20.2%) in the NAC plus CCRT group versus CCRT group with statistically significant differences. The addition of NAC to CCRT was associated with better DFS for the high-risk group of elderly LANPC patients with ACE-27 score <2. However, the survival benefit of additional NAC was not observed in low-risk patients.

CAR-T lymphocyte-based cell therapies; mechanistic substantiation, applications and biosafety enhancement with suicide genes: new opportunities to melt side effects.

Immunotherapy has made significant strides in cancer treatment with strategies like checkpoint blockade antibodies and adoptive T cell transfer. Chimeric antigen receptor T cells (CAR-T) have emerged as a promising approach to combine these strategies and overcome their limitations. This review explores CAR-T cells as a living drug for cancer treatment. CAR-T cells are genetically engineered immune cells designed to target and eliminate tumor cells by recognizing specific antigens. The study involves a comprehensive literature review on CAR-T cell technology, covering structure optimization, generations, manufacturing processes, and gene therapy strategies. It examines CAR-T therapy in haematologic cancers and solid tumors, highlighting challenges and proposing a suicide gene-based mechanism to enhance safety. The results show significant advancements in CAR-T technology, particularly in structure optimization and generation. The manufacturing process has improved for broader clinical application. However, a series of inherent challenges and side effects still need to be addressed. In conclusion, CAR-T cells hold great promise for cancer treatment, but ongoing research is crucial to improve efficacy and safety for oncology patients. The proposed suicide gene-based mechanism offers a potential solution to mitigate side effects including cytokine release syndrome (the most common toxic side effect of CAR-T therapy) and the associated neurotoxicity.

Correlation of gut microbiota with leukopenia after chemotherapy in patients with colorectal cancer

BackgroundThe most common toxic side effect after chemotherapy, one of the main treatments for colorectal cancer (CRC), is myelosuppression.ObjectiveTo analyze the correlation between gut microbiota and leukopenia after chemotherapy in CRC patients.MethodsStool samples were collected from 56 healthy individuals and 55 CRC patients. According to the leukocytes levels in peripheral blood, the CRC patients were divided into hypoleukocytes group (n = 13) and normal leukocytes group (n = 42). Shannon index, Simpson index, Ace index, Chao index and Coverage index were used to analyze the diversity of gut microbiota. LDA and Student's t-test(St test) were used for analysis of differences. Six machine learning algorithms, including logistic regression (LR) algorithm, random forest (RF) algorithm, neural network (NN) algorithm, support vector machine (SVM) algorithm, catboost algorithm and gradient boosting tree algorithm, were used to construct the prediction model of gut microbiota with leukopenia after chemotherapy for CRC.ResultsCompared with healthy group, the microbiota alpha diversity of CRC patients was significantly decreased (p < 0.05). After analyzing the gut microbiota differences of the two groups, 15 differential bacteria, such as Bacteroides, Faecalibacterium and Streptococcus, were screened. RF prediction model had the highest accuracy, and the gut microbiota with the highest predictive value were Peptostreptococcus, Faecalibacterium, and norank_f__Ruminococcaceae, respectively. Compared with normal leukocytes group, the microbiota alpha diversity of hypoleukocytes group was significantly decreased (p < 0.05). The proportion of Escherichia-Shigella was significantly decreased in the hypoleukocytes group. After analyzing the gut microbiota differences of the two groups, 9 differential bacteria, such as Escherichia-Shigella, Fusicatenibacter and Cetobacterium, were screened. RF prediction model had the highest accuracy, and the gut microbiota with the highest predictive value were Fusicatenibacte, Cetobacterium, and Paraeggerthella.ConclusionGut microbiota is related to leukopenia after chemotherapy. The gut microbiota may provide a novel method for predicting myelosuppression after chemotherapy in CRC patients.

Coenzyme Q10 and N-acetyl cysteine modulates the haematological parameters, markers of oxidative stress and membrane bound phosphatase in spleen toxicity induced by aniline hydrochloride

Aniline is widely used chemical for industrial purpose. Exposure to aniline can lead to various health issues in human being. The most common toxic effect of aniline is splenotoxicity which is produced via the generation of oxidative stress. The present study examines the protective effect of coenzyme Q10 and N-acetyl cysteine on spleen weight, body weight, endogenous antioxidants and membrane bound ATPases in aniline hydrochloride (AH) induced spleen toxicity in rats. Adult male albino rats were divided into five groups, each group consists of six rats. Toxicity was induced by administration of AH (100 ppm, p. o) in drinking water for 30 days. Body weight, markers of oxidative stress and haematological parameters were assessed at the end of treatment period. Treatment rats received Coenzyme Q10 (CoQ10, 10 mg/kg/day/p.o) and N- acetyl cysteine (NAC, 300mg/kg/ day p.o) alone and in combination for 30. AH toxic rats showed a significant elevation of spleen weight, WBC count, iron content, LPO level, NO level and Ca ATPase whereas a significant decrease in body weight, haemoglobin, RBCs level, Protein content, GSH and Na/ K and Mg ATPase were observed. Administration of Coenzyme Q10 (CoQ10, 10 mg/kg/day/p.o) and N- acetyl cysteine (NAC, 300mg/kg/ day p.o) together for 30 consecutive days shows a significant decrease in spleen weight, WBC level, iron content, LPO level, NO level whereas significant increase in body weight, hemoglobin level, RBCs level Protein content, GSH level, Na/ K ATPase, Ca and Mg ATPase when compared with aniline treated group and CoQ10 or NAC alone treated groups. These findings indicate the synergistic &amp; protective effect of CoQ10 and NAC in aniline induced spleen toxicity in rats compared to alone antioxidants.

Occurrence and progression of osseo-muscular and neurologic manifestations in Wilson’s disease

Osseo-muscular presentations of Wilson’s Disease (WD) are not common, but have been reported in several studies from different parts of the world. We studied a group of 36 patients who presented with prominent osseo-muscular affection and were ultimately diagnosed with WD. We studied the pattern of osseo-muscular involvement in these patients and also the specific neurologic manifestations that they manifested. We also followed up these patients who were being given optimal dietary and pharmacologic treatment over a period of 2 years to analyze the response of osseo-muscular and neurologic disease to treatment. The results showed that osseo-muscular involvement in WD patients are nonspecific and involve bone demineralization and joint inflammation predominantly. Presence of proximal myopathy with normal creatine phosphokinase level but electrophysiological evidence of myopathy was notable in this study. Neurologic involvement was mainly dystonic and cerebellar with the notable absence of significant tremor. Adequate therapy resulted in salutary improvement or stabilization of both neurologic and osseo-muscular involvement, indicating a possible common toxic effect of excess copper on both neuronal and musculoskeletal tissue. Further studies are required to document the biochemical and toxicologic pathways causing cellular and tissue damage in WD.

Maligni tumori kostiju kod dece u Iraku

Introduction/Aim. Roughly six percent of all malignancies diagnosed in children are malignant bone tumors. They have a dramatic effect on psychological status of children and their families. The aim of the study was to analyze the clinico-pathological features of bone tumors in Iraqi children and to assess response to treatment, outcome, and survival. Patients and methods. Over an eleven-year period, a retrospective study was done for children with bone tumors conducted on patients data that included a battery of pre-treatment investigations including a complete blood count, serum electrolyte, hepatic, and renal profile, bone marrow aspirate and biopsy, fine-needle aspiration, and imaging studies. Results. Data of 41 children with bone tumor were collected. The most common site of involvement was lower limbs, found in 21 (51.2%) cases. At the time of diagnosis, 29 patients presented with localized disease (70.7%), while 12 (29.3%) patients presented with metastasis. From 41 patients included in the study, histopathology of 29 (70.7%) patients was Ewing's sarcoma, whereas 12 (29.3%) patients were diagnosed with osteogenic sarcoma. The most common toxic effect of chemotherapy was febrile neutropenia which was recorded in 22 (59.5%) patients, followed by hemorrhagic cystitis in 3 (8.1%) patients; both febrile neutropenia and hemorrhagic cystitis were recorded in 5 (13.5%) patients, convulsion was found in 1 (2.7%) patient, and no complication were reported in 5 (13.5%) patients. Relapse was found in 8 (21.6%) patients. Conclusion. High rate of patients were lost to follow-up. Two-year event-free survival (EFS) was 53%, which is lower than that reported in other studies due to late diagnosis, late referral with the presentation in the locally advanced stage of disease.

357: MORE THAN MYALGIA: STATIN-INDUCED IMMUNE-MEDIATED NECROTIZING MYOPATHY

Introduction: Statins rank amongst the top ten most prescribed medications in the United States for their cardiovascular benefits. Common toxic side effects include elevated liver enzymes and myalgia including rhabdomyolysis. We report a case of a previously healthy middle-aged female who recently started statin therapy and developed progressive muscle weakness requiring mechanical ventilation. Description: A 58-year-old female with recently diagnosed hyperlipidemia started on atorvastatin (40 mg) 2 months prior to presentation was admitted with 2 weeks of progressively worsening proximal muscle weakness and oropharyngeal dysphagia. Admission labs showed a significantly elevated creatine phosphokinase (CPK) (3,742 U/L) and aldolase level (41.1 U/L). She was empirically started on IVIG for presumed myasthenic crisis or possible inflammatory myositis. On day 2, she exhibited worsening proximal muscle weakness and an inability to lift her extremities against gravity. On physical exam, she had 1/5 strength of proximal muscle groups and 4/5 strength of distal muscle groups with an otherwise intact neuromuscular exam. On day 3, she had worsening dysphagia and aspiration pneumonitis requiring endotracheal intubation. An EMG showed myopathic features in the proximal musculature without any evidence of neuropathy. She was empirically started on steroids with some improvement. After 1 week, the anti-HmgCoA reductase antibody returned severely positive (>200). Given the high specificity of this test, her presentation was ultimately deemed consistent with statin induced immune-mediated necrotizing myopathy, and she was started on Cellcept (MMF) and high-dose steroids. Discussion: The case highlights the devastating consequences that can result from a very commonly prescribed medication class and the importance of actively evaluating for adverse medication effects. Statin therapies are guideline directed in patients with cardiovascular disease such as coronary artery disease and stroke. Myalgia without significant weakness are a common side effect and therapy includes discontinuing the offending agent. In the presence of severe weakness, statin induced immune-mediated necrotizing myopathy should be considered, as it could be detrimental and may require mechanical ventilation and treatment with immunosuppressants.

Mechanism and research progress of classical prescriptions and non-classical prescriptions in prevention and treatment of side effects of radiotherapy and chemotherapy

Although targeted therapy and immunotherapy will become the trend of systematic therapy for tumor in the future, radiotherapy and chemotherapy are still regarded as one of the main means to treat cancer due to their low price and wide application. The toxic and side effects of radiotherapy and chemotherapy can limit the therapeutic effect and affect the body immunity, which is very difficult to deal with by modern medical means, and in this process, patients are prone to develop resistance to the application of radiotherapy and chemotherapy, which makes it difficult to implement follow-up treatment, leading to disease progression and ultimately affecting the prognosis of patients. In recent years, a large number of traditional Chinese medicine(TCM)-related clinical studies have found that classical prescriptions and non-classical prescriptions can markedly alleviate the toxic and side effects caused by radiotherapy and chemotherapy, with clear and significant efficacy, and to some extent, they can improve the quality of life and prolong the survival period of patients. Therefore, TCM decoction may provide new opportunities for intervening in the refractory and high-incidence toxic and side effects. To further explore the application of classical prescriptions and non-classical prescriptions in tumor, this study reviewed the mechanism of toxic and side effects caused by radiotherapy and chemotherapy, the mechanism of classical prescriptions and non-classical prescriptions in the treatment of toxic and side effects, and the classical prescriptions and non-classical prescriptions used for treating common toxic and side effects in recent five years. This study was expected to promote the application and development of classical prescriptions and non-classical prescriptions in the field of cancer treatment by systematically summarizing their research progress in the prevention and treatment of toxic and side effects caused by radiotherapy and chemotherapy.

Targeting Calcineurin Inhibitor-Induced Arterial Hypertension in Liver Transplanted Children Using Hydrochlorothiazide.

Arterial hypertension (AH) is the most common toxic effect of calcineurin inhibitor (CNI)-based immunosuppression in children after liver transplantation (LT). Activation of the renal sodium chloride cotransporter (NCC) by CNIs has been described as a major cause of CNI-induced AH. Thiazides, for example, hydrochlorothiazide (HCTZ), can selectively block the NCC and may ameliorate CNI-induced AH after pediatric LT. From 2005 thru 2015 we conducted a retrospective, single-center analysis of blood pressure in 2 pediatric cohorts (each n = 33) with or without HCTZ in their first year after LT. All patients received CNI-based immunosuppression. According to AAP guidelines, AH was defined as stage 1 and stage 2. Cohort 1 received an HCTZ-containing regimen to target the CNI-induced effect on the NCC, leading to AH. Cohort 2 received standard antihypertensive therapy without HCTZ. In children who have undergone LT and been treated with CNI, AH overall was observed less frequently in cohort 1 vs cohort 2 (31% vs 44%; ns). Moreover, severe AH (stage 2) was significantly lower in cohort 1 vs 2 (1% vs 18%; p < 0.001). Multivariate analysis revealed HCTZ as the only significant factor with a protective effect on occurrence of severe stage 2 AH. While monitoring safety and tolerability, mild asymptomatic hypokalemia was the only adverse effect observed more frequently in cohort 1 vs 2 (27% vs 3%; p = 0.013). Targeting NCC by HCTZ significantly improved control of severe CNI-induced AH and was well tolerated in children who underwent LT. This effect may reduce the risk of long-term end-organ damage and improve quality of life.

Impact of Parenteral Glutamine Supplement on Oncologic Outcomes in Patients with Nasopharyngeal Cancer Treated with Concurrent Chemoradiotherapy.

Background: Oral mucositis (OM) is a common toxic side effect in nasopharyngeal carcinoma (NPC) patients receiving concurrent chemoradiotherapy (CCRT) that has a negative impact on treatment outcomes and patients’ survival. Our study aimed to evaluate the impact of parenteral glutamine supplement (dipeptiven) on oncologic outcomes in patients with NPC treated with CCRT. Methods: Patients who were diagnosed with pathologically proved NPC and treated with CCRT were enrolled into our study. Patients were classified as dipeptiven (+) and dipeptiven (–). Oncologic outcomes were measured, and multivariate regression analysis was performed. Grade 3–4 treatment related toxicities were also documented. Results: A total of 144 patients with NPC were recruited in this study to evaluate oncologic outcomes, with 41 dipeptiven (+) and 103 dipeptiven (–). CCRT interruption rate and severe adverse effect (SAE) rate were significant lower in the dipeptiven (+) group than in the dipeptiven (–) group. The median overall survival (OS) was not mature yet in the dipeptiven (+) group and 30 months in the dipeptiven (–) group (p < 0.01). Multivariate analysis demonstrated that dipeptiven supplementation and CCRT interruption were independent predictors associated with better survival. The OS was longest in patients with a dipeptiven supplement and patients who had CCRT interruption had significantly worst OS. As for safety profiles, grade 3 to 4 adverse effects were fewer in dipeptiven (+) than in dipeptiven (–). Conclusion: Dipeptiven supplementation is crucial in NPC patients treated with CCRT, which can ameliorate treatment-related toxicity and augment treatment efficacy. Further prospective clinical trials are warranted to validate our results.

The grouping of chemicals with effects on reproduction and development for the purpose of cumulative risk assessment in Europe

The European Food Safety Authority (EFSA) is developing approaches for cumulative risk assessment by assigning chemicals (pesticides) to cumulative assessment groups (CAGs) based on common toxic effects on the target system. This document a reviews and refines the approach for reproduction and developmental toxicity published in 2016, to identify relevant substances for grouping with guidance for discriminating between direct effects on the reproductive system or on development of the offspring and those effects which are secondary to other toxicities. The refined approach is then considered in relation to the Classification, Labelling & Packaging (CLP) criteria based on which pesticides are classified for adverse effects on sexual function and fertility, for adverse effects on development of the offspring or for adverse effects on or via lactation. The proposed grouping of effects and accompanying guidance are intended to facilitate knowledge-based interpretation of data from test guideline reproduction and developmental toxicity studies for the purpose of cumulative risk assessment.

Comparative toxicity study of waterborne two booster biocides (CuPT and ZnPT) on embryonic flounder (Paralichthys olivaceus)

A new generation of booster biocides that include metal pyrithiones (PTs) such as copper pyrithione (CuPT) and zinc pyrithione (ZnPT) are being used as tributyltin alternatives. In the marine environment, ZnPT can easily transchelate Cu to form CuPT, and the environmental fate and persistence of these two metal pyrithiones are closely related. Although some data on the toxicity of biocides on marine fish are available, little is known about their toxicity and toxic pathway. We thus compared the toxic effects of CuPT and ZnPT on embryonic olive flounder (Paralichthys olivaceus) by investigating their adverse effects based on developmental morphogenesis and transcriptional variation. In our study, the toxic potency of CuPT was greater with respect to developmental malformation and mortality than ZnPT. Consistent with the developmental effects, the expression of genes related to tail fin malformation (including plod2, furin, and wnt3a) was higher in embryonic flounder exposed to CuPT than in those exposed to ZnPT. Genes related to muscle and nervous system development exhibited significant changes on differential gene expression profiles using RNA sequencing (cutoff value P < 0.05). Gene ontology analysis of embryos exposed to CuPT revealed affected cellular respiration and kidney development, whereas genes associated with cell development, nervous system development and heart development showed significant variation in embryonic flounder exposed to ZnPT. Overall, our study clarifies the common and unique developmental toxic effects of CuPT and ZnPT through transcriptomic analyses in embryonic flounder.

Development and Internal Validation of a Recursive Partitioning Analysis–Based Model Predictive of Pain Flare Incidence After Spine Stereotactic Body Radiation Therapy

PurposePain flares are a common acute toxic effect after stereotactic body radiation therapy (SBRT) for spine metastasis. We aimed to identify a subset of patients with the highest rate of pain flare after spine SBRT to optimize prophylactic corticosteroid administration. Methods and MaterialsThe data set included 428 patients with 610 treatments. We defined pain flare as acute worsening of pain at the treatment site requiring new or higher dose therapy with corticosteroids, opiates, and/or hospitalization. Data were split into 70% training and 30% validation sets using a random number generator. After feature importance testing and generation of a correlation heatmap, feature extraction was performed via recursive partitioning analysis. ResultsWe identified 125 total pain flares (20%). Five variables met significance (P < .02) for model inclusion: renal primary, soft tissue involvement, Bilsky >0, spinal instability neoplastic score >6, and gross tumor volume >8 cc. One point was assigned for each variable. The low-risk group (score = 0, n = 159) had pain flare rates of 7.0% and 13.6% in the training and validation sets; the intermediate-risk group (score = 1, n = 150) had rates of 14.0% and 16.3%; and the high-risk group (score >1, n = 301) had rates of 28.8% and 31.3%. Patients in the high-risk group had higher rates of flare (odds ratio, 3.50; 95% confidence interval, 2.06-5.92) and accumulated health care costs 3 and 6 months post-SBRT, relative to intermediate- and low-risk patients (P < .001). ConclusionsOur internally validated model identifies a high-risk group of patients more likely to develop a pain flare after spine SBRT, for whom prophylactic steroids may be considered. Evaluation in a clinical trial is warranted.

Intensity Modulated Proton Therapy for Bilateral Breast or Chest Wall and Comprehensive Nodal Irradiation for Synchronous Bilateral Breast Cancer: Initial Clinical Experience and Dosimetric Comparison

PurposeSynchronous bilateral breast cancer (SBBC) poses distinct challenges for radiation therapy planning. We report our proton therapy experience in treating patients with SBBC. We also provide a dosimetric comparison of intensity modulated proton therapy (IMPT) versus photon therapy. Methods and MaterialsPatients with SBBC who received IMPT at our institution were retrospectively analyzed. The clinical target volume (CTV) included the breast or chest wall and comprehensive regional lymph nodes, including axilla, supraclavicular fossa, and the internal mammary chain. Intensity modulated proton therapy and volumetric modulated arc therapy (VMAT) plans were generated with the goal that 90% of the CTV would recieve at least 90% of the prescription dose (D90>=90%). Comparisons between modalities were made using the Wilcoxon signed rank test. Physician-reported acute toxic effects and photography were collected at baseline, end of treatment, and each follow-up visit. ResultsBetween 2015 and 2018, 11 patients with SBBC were treated with IMPT. The prescription was 50 Gy in 25 fractions. The median CTV D90 was 99.9% for IMPT and 97.6% for VMAT (P = .001). The mean heart dose was 0.7 Gy versus 7.2 Gy (P = .001), the total lung mean dose was 7.8 Gy versus 17.3 Gy (P = .001), and the total lung volume recieving 20 Gy was 13.0% versus 27.4% (P = .001). The most common acute toxic effects were dermatitis (mostly grade 1-2 with 1 case of grade 3) and grade 1 to 2 fatigue. The most common toxic effects at the last-follow up (median, 32 months) were grade 1 skin hyperpigmentation, superficial fibrosis, and extremity lymphedema. No nondermatologic or nonfatigue adverse events of grade >1 were recorded. ConclusionsBilateral breast and/or chest wall and comprehensive nodal IMPT is technically feasible and associated with low rates of severe acute toxic effects. Treatment with IMPT offered improved target coverage and normal-tissue sparing compared with photon therapy. Long-term follow-up is ongoing to assess efficacy and toxic effects.

Induction Therapy Followed by Surgery for Unresectable Thymic Epithelial Tumours.

Background and ObjectivesThe treatment of unresectable thymic epithelial tumours (TETs) remains controversial. Here, we present the efficacy and safety of induction therapy followed by surgery for unresectable TET.MethodsEighty-one patients with unresectable TETs treated with induction therapy followed by surgery were selected from a retrospective review of consecutive TETs from January 2005 to January 2021. Clinicopathological data were analyzed to assess tumour responses, resectability, adverse events, progression-free survival (PFS) and overall survival (OS).ResultsInduction therapy produced a major tumour response rate of 69.1%, a tumour response grade (TRG) 1-3 rate of 84.0% and an R0 resection rate of 74.1%. The most common toxic effects were all-grade neutropenia (35.8%) and anaemia (34.6%). The 10-year OS and PFS rates were 45.7% and 35.2%. Multivariate analysis showed that ypTNM stage, ypMasaoka stage, complete resection, and TRG were significant independent prognostic factors. Exploratory research revealed that different induction modalities and downstaging of T, N, M, TNM, or Masaoka classifications did not significantly alter the pooled hazard ratio for survival.ConclusionsInduction therapy followed by surgery is well tolerated in patients with unresectable TETs, with encouraging R0 resection rates. Multimodality management provides good control of tumors for unresectable TET patients.

Analysis of the Outcome of Treatment of Brain Metastases from Malignant Trophoblastic Tumours and Risk Factors for Prognosis during Pregnancy.

Temozolomide combined with whole-brain radiotherapy has good near-term efficacy and safety in the treatment of brain metastases from nonsmall cell lung cancer. In this study, we analyzed the risk factors for treatment and prognosis of brain metastases in gestational trophoblastic neoplasm (GTN) during pregnancy. Thirty-one patients with brain metastases were included in the study. All patients had a pathological diagnosis of primary lesions, including 23 adenocarcinomas, 7 squamous carcinomas, and 1 adenosquamous carcinoma, and had ≥3 intracranial metastases, controlled primary lesions (including resected primary lesions or unresectable primary lesions in partial remission (PR)/complete remission (CR) for ≥2 months) by cranial enhancement MRI and no extracranial metastases. Presence or control of extracranial metastases was for ≥2 months. The common adverse toxic effects were nausea, vomiting, neutropenia, and thrombocytopenia, but most patients tolerated them with symptomatic management.